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What Makes Oncology Clinical Research Ethical?


AIDS clinical trials (late 1980's) 7. Codes Of Research Ethics. Nuremberg Code (1947) ... Benefits of a clinical trial must justify the risks ... – PowerPoint PPT presentation

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Title: What Makes Oncology Clinical Research Ethical?

What Makes OncologyClinical Research Ethical?
  • Steven Joffe, MD, MPH
  • Assistant Professor of Pediatrics

  • Understand the ethical tensions in the
    investigator-subject relationship
  • Learn a systematic approach to evaluating the
    ethics of oncology trials
  • Understand how to improve the consent process for
    cancer clinical research
  • Consider the challenges raised by con-flicts of
    interest in oncology research

  • Patients with imatinib-refractory GIST
  • Offered participation in RCT of sunitinib vs.
  • open-label access to drug at progression
  • two prestigious medical centers, MD Anderson U
    of Michiganrefused to join in

Mishra R. Placebos break taboo in cancer drug
tests. Boston Globe, A1, July 4, 2004
Case (Contd)
  • When patients have an advanced cancer the
    cancer is growing, there isnt any way the
    placebo can be helpful to the patient. To
    argue that a placebo trial is in societys
    interests has nothing to do with helping these
  • Assoc. Director, U of Michigan Cancer Center
    (quoted in R. Mishra, Boston Globe, July 4, 2004)

History Of Research Ethics
  • Landmark events
  • Nazi experiments
  • Willowbrook hepatitis studies (1956-72)
  • Jewish Chronic Disease Hospital studies (1963)
  • Henry Beechers NEJM article (1966)
  • Tuskegee Syphilis Study (1932-72)
  • AIDS clinical trials (late 1980s)

Codes Of Research Ethics
  • Nuremberg Code (1947)
  • informed consent, societal value, unacceptable
    levels of risk
  • Declaration of Helsinki (orig. 1964)
  • added written protocol, independent review
  • Belmont Report (1979)
  • added justice, fair subject selection

Key U.S. Regulatory Documents
  • 45 Code of Federal Regulations 46 (45 CFR 46)
  • Common Rule
  • Subpart D Pediatric regulations
  • 21 CFR 50 56 (FDA regulations)
  • Privacy Rule under HIPAA (2003)

Definition of Clinical Research
  • research class of activities designed to
    develop or contribute to generalizable knowledge
  • practice interventions designed solely to
    enhance the well being of an individual patient
    or client

Belmont Report, 1979
The Clinician-Investigator
  • Dual allegiance
  • to study/community
  • to patient/subject
  • Creates a (legitimate) conflict of interest
  • Important to be aware of this tension
  • Miller et al. JAMA 2801449

Example Of Conflict
  • NSABP trials--1994
  • PI at St. Luc Hospital in Montreal falsified
    procedure dates and hormone-receptor status so
    that breast cancer patients would appear to meet
    eligibility criteria for a clinical trial

PI Response
  • My sole concern at all times was the health of
    my patients. I firmly believed that a patient
    who was able to enter into an NSABP trial
    received the best therapy and follow-up
    treatment. For me, it was difficult to tell a
    woman with breast cancer that she was ineligible
    to receive the best available treatment because
    she did not meet 1 criteria out of 22

Poisson R. N Engl J Med3301460
Criteria for Ethical Research
  • Social value
  • Scientific validity
  • Fair subject selection
  • Reasonable balance of risks benefits
  • Independent review
  • Informed consent
  • Respect for enrolled subjects

Emanuel et al. JAMA 283 2701
Social Value
  • Study must ask an important question
  • valuable for improving health and/or for basic
    scientific knowledge
  • research is unethical if question is trivial, has
    already been answered, etc.

Scientific Validity
  • Even if question is important, study is unethical
    if methods arent likely to answer it
  • not feasible
  • poor measures
  • inadequate sample size
  • poor statistical analysis
  • biased reporting (or non-reporting)

Fair Subject Selection
  • Historically, risky or non-beneficial research
    has disproportionately enrolled vulnerable
  • ethnic minorities
  • mentally incapacitated, institutionalized
  • Conversely, exclusion of certain groups from
    research disenfranchises them from benefits of
    the knowledge gained

Risk/Benefit Balance
  • Benefits of a clinical trial must justify the
  • sometimes, the risk/benefit ratio for the
    participant is clearly unfavorable
  • e.g., research-related biopsies

Risk/Benefit Balance
  • Benefits of a clinical trial must justify the
  • sometimes, the risk/benefit ratio for the
    participant is clearly unfavorable
  • e.g., research-related biopsies

Risk/Benefit Balance
  • To approve a study, the IRB must find that
  • risks to subjects are reasonable in relation to
    anticipated benefits, if any, to subjects, and
    the importance of the knowledge that may
    reasonably be expected to result

45 CFR 46.111(a)(2)
Independent Review
  • Institutional Review Boards (IRBs)
  • independent review is mandated by federal
    regulation for most research with human subjects
  • IRBs review studies at inception
  • science, risk/benefit ratio, informed consent
  • IRBs also monitor studies as they proceed
  • continuing reviews, amendments
  • adverse events, unanticipated problems

Informed Consent
  • Ensure respect for individuals values
    preferences in decisions about their medical care
    research participation
  • respect for patient/subject autonomy
  • View as ongoing process, not one-time event

Components Of Valid Consent
  • Voluntariness
  • Undermined by coercion, not by incentives,
    life-threatening disease
  • Capacity
  • Disclosure
  • Undermined by deception, manipulation
  • Understanding
  • Decision

Basic Elements of Research Consent
  • nature of research, purpose, duration,
    procedures, what is experimental
  • risks
  • benefits to self others
  • alternatives
  • implications for confidentiality
  • research-related injury compensation
  • whom to contact
  • consent is voluntary freedom to withdraw
  • 45 CFR 46

The Therapeutic Misconception
  • the belief that the purpose of a clinical trial
    is to benefit the individual patient rather than
    to gather data for the purpose of contributing to
    scientific knowledge. It is not a misconception
    to believe that participants probably will
    receive good clinical care during research. But
    it is a misconception to believe that the purpose
    of clinical trials is to administer treatment
    rather than to conduct research

National Bioethics Advisory Commission Ethical
and Policy Issues in International Research 2001
Factors Associated WithImproved Understanding
  • Patient-subject
  • discussion in primary language
  • higher education/SES
  • younger age (geriatric patients at risk)

Factors Associated WithImproved Understanding
  • Consent process
  • reading consent form carefully
  • receiving template-based consent form
  • having a 3rd party present at discussion
  • having time to review consent form
  • more detailed information (to a point)
  • more readable forms
  • intensive educational process

Strategy For Soliciting Informed Consent
  1. Structured, planned approach
  2. Clarify how participation in the study differs
    from standard care
  3. Be honest about uncertainty
  4. Discuss how participation in trials serves a
    critical public good

Example of a Structured Approach
Understand disease clinical status
Understand current treatment
Understand clinical trial
Pediatrics 119e849 (2007)
Writing a Great Consent Form
  • Use a template to structure your form
  • Start w/ We are inviting you to take part 
  • Avoid unqualified use of treatment to describe
    study interventions 
  • Use a user-friendly, conversational style
  • Format the consent form in a way that facilitates
    easy reading
  • (See http//www.cancer.gov/clinicaltrials/understa

Respect For Subjects
  • Share new information
  • Avoid conflicts of interest
  • Maintain confidentiality
  • Show gratitude for subjects contributions
  • Inform subjects of results

A Few Words About Conflicts of Interest
  • Definition
  • a COI occurs when a professional judgment
    concerning a primary interesttends to be unduly
    influenced by a secondary interest

NEJM 29573, 1993
Interests In Research
  • Primary
  • Valid, valuable science
  • Including dissemination of research results
  • Respect for welfare of subjects
  • Secondary
  • Non-financial
  • Promotions
  • Publications
  • Prestige
  • Financial
  • Research funding
  • Income

Potential ConsequencesOf Conflicts Of Interest
  • Decreased communication of research findings,
    scientific openness
  • Bias in research
  • design
  • conduct
  • analysis
  • reporting
  • Increased risks to human subjects

Bekelman JE, JAMA 289454, 2003
Guidelines Re Conflict of Interest
  • Avoid where possible
  • Minimize or manage
  • Disclose
  • In industry-sponsored research, ensure
    contractual rights to data access, publication,

  • Ethical guidance is needed to prevent
    exploitation of subjects in research
  • 7 principles offer systematic approach to
    determining whether a study is ethical
  • Balancing of principles when applied to
    particular trials can be complex
  • Clarity about conflicts of interest can help
    investigators navigate this difficult issue

Reflections On Case
  • Purpose of study is to validate efficacy of
    sunitinib for imatinib-refractory GIST
  • Not to be helpful to the patient
  • Critical questions
  • Will participants be worse off inside than
    outside the study?
  • Can alternate design provide valid answer?
  • Does design minimize risk maximize be-nefit,
    consistent w/ obtaining valid results?

Important Elements of Informed Consent
  • Statement that the study involves research
  • Statement that participation is voluntary
  • Visual protocol schema
  • Description of foreseeable risks
  • Description of any benefits
  • Disclosure of appropriate alternatives
  • Explanation of whether compensation for injury is
  • Statement describing the degree to which
    identifiable records will be kept confidential
  • Name of person to contact for answers to

Additional Elements of Informed Consent
  • May include information about
  • Risks to the participant that are unanticipated
  • Circumstances when participation may be
    terminated by the investigator
  • Additional costs to the participant
  • Consequences of the decision to withdraw
  • Significant new finding and whether and/or when
    they will be shared with participants
  • Approximate number of individuals in the study

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